The primary objectives of the proposed investigation are: 1) To define more clearly the mechanisms of the cardiovascular effects of 1-alpha-acetylmethadol (LAAM) and congeners. 2) To determine the therapeutic and toxicological significance of such effects. 3) To identify pharmacological and environmental factors that influence the disposition of LAAM. 4) To determine whether or not changes in LAAM disposition alter cardiovascular responses to the drug. Current work in this laboratory has shown that LAAM, an investigational drug, has negative inotropic and chronotropic effects on isolated guinea pig atria. The significance of these effects will be identified by the first two objectives. These objectives will be achieved with the following general series of experiments:1) Studies on cardiac effects of LAAM on isolated atria from additional species (naive animals). 2) Studies on atria from guinea pigs treated chronically with LAAM. 3) Acute experiments on the naive anesthetized dog. 4) Experiments on unanesthetized dogs which received LAAM chronically. Cardiovascular responses to be monitored in the last two groups of experiments include heart rate, arterial blood pressure and myocardial contractile force (3 only). Drug interactions between LAAM and other cardioactive agents as well as cardiovascular effects of LAAM in debilitated animals will be studied. The pattern of disposition for LAAM in normal dogs following acute administration will be compared with that in animals that are treated chronically with the drug. Effects of many pharmacological and toxicological interventions, including chronic morphine and methadone treatments, on LAAM disposition will be investigated. LAAM and metabolites will be identified by gas-liquid chromatography or a combination of gas-liquid chromatography and mass spectrometry. All of the experiments outlined above must be completed and the data obtained thoroughly evaluated before LAAM can be used effectively and safely in the treatment of opiate addiction.